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Evaluation of VX 445/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age

Primary Purpose

Cystic Fibrosis

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

ELX/TEZ/IVA

IVA

About this trial

This is an interventional treatment trial for Cystic Fibrosis

Eligibility Criteria

6 Years - 11 Years (Child)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria:

Homozygous or heterozygous for F508del mutation (F/F or F/MF genotypes)
Forced expiratory volume in 1 second (FEV1) value ≥40% of predicted mean for age, sex, and height.

Key Exclusion Criteria:

Clinically significant cirrhosis with or without portal hypertension
Lung infection with organisms associated with a more rapid decline in pulmonary status.
Solid organ or hematological transplantation.

Other protocol defined Inclusion/Exclusion criteria may apply.

Sites / Locations

Children's Hospital of Orange County
Children's Hospital Colorado
Ann & Robert Lurie Children's Hospital of Chicago
Boston Children's Hospital
Children's Respiratory and Critical Care Specialists, P.A., Children's Hospitals and Clinics of Minnesota
The Children's Mercy Hospital
Northwell Health- Long Island Jewish Medical Center
Clinical Research of Charlotte
Rainbow Babies and Children's Hospital/University Hospitals Cleveland Medical Center
Nationwide Children's Hospital
Oregon Health & Science University
Texas Children's Hospital
Seattle Children's Hospital
Queensland Children's Hospital
The Children's Hospital at Westmead
The Hospital for Sick Children
British Columbia's Children's Hospital
Children's Health Ireland at Crumlin
Children's Health Ireland at Temple Street
Birmingham Children's Hospital
Royal Brompton & Harefield NHS Foundation Trust, Royal Brompton Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Part A: ELX/TEZ/IVA

Part B: ELX/TEZ/IVA

Arm Description

Participants in Part A received ELX 100 milligrams (mg) once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) in the treatment period for 15 days.

Participants in Part B weighing less than (<) 30 kilograms (kg) at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing greater than equals to (>=) 30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.

Outcomes

Primary Outcome Measures

Part A: Maximum Observed Plasma Concentration (Cmax) of ELX, TEZ, and IVA

Part A: Observed Pre-dose Plasma Concentration (Ctrough) of ELX, TEZ, and IVA

Part A: Area Under the Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24h) of ELX, TEZ, and IVA

Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Secondary Outcome Measures

Part A: Cmax of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)

Part A: Ctrough of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)

Part A: AUC0-24h of ELX Metabolite (M23-ELX) and TEZ Metabolite (M1-TEZ)

Part A: Area Under the Concentration Versus Time Curve From 0 to 6 Hours (AUC0-6h) of IVA Metabolite (M1-IVA)

The AUC data was analyzed for up to 6 hours for IVA metabolite (M1-IVA). Therefore, AUC0-6h is reported for M1-IVA metabolite.

Part A: Safety and Tolerability as Assessed by Number of Participants With TEAEs and SAEs

Part B: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Part B: Absolute Change in Sweat Chloride (SwCl)

Sweat samples were collected using an approved collection device.

Part B: Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score

The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.

Part B: Absolute Change in Body Mass Index (BMI)

BMI was defined as weight in kg divided by squared height in meters (m^2).

Part B: Absolute Change in BMI For-Age Z-Score

BMI was defined as weight in kg divided by squared height in meters (m^2). The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

Part B: Absolute Change in Weight

Part B: Absolute Change in Weight-for-age Z-Score

The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

Part B: Absolute Change in Height

Part B: Absolute Change in Height-for-Age Z-Score

Part B: Drug Acceptability Assessment Using Modified Facial Hedonic Scale

The study drug acceptability (participant reaction) was assessed by a visual analog scale that incorporates a 5 point facial hedonic scale (Liked it Very Much, Liked it a Little, Not sure, Disliked it a Little, Disliked it Very Much). Number of participants with the indicated categorical response in the drug acceptability assessment were reported.

Part B: Number of Pulmonary Exacerbations Events

Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol defined criteria. The total number of pulmonary exacerbations events across all participants were reported.

Part B: Number of CF Related Hospitalizations

The total number of CF related hospitalization events across all participants were reported.

Part B: Ctrough of ELX, ELX Metabolite (M23-ELX), TEZ, TEZ Metabolite (M1-TEZ), IVA and IVA Metabolite (M1-IVA)

Part B: Absolute Change in Lung Clearance Index 2.5 (LCI2.5)

LCI 2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.

Full Information

NCT ID

NCT03691779

First Posted

September 28, 2018

Last Updated

September 24, 2021

Sponsor

Vertex Pharmaceuticals Incorporated

1. Study Identification

Unique Protocol Identification Number

NCT03691779

Brief Title

Evaluation of VX 445/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age

Official Title

A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of VX-445/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 Through 11 Years of Age

Study Type

Interventional

2. Study Status

Record Verification Date

August 2021

Overall Recruitment Status

Completed

Study Start Date

October 2, 2018 (Actual)

Primary Completion Date

August 7, 2020 (Actual)

Study Completion Date

August 7, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Vertex Pharmaceuticals Incorporated

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

This study will evaluate the pharmacokinetics (PK), safety, tolerability, efficacy, and pharmacodynamic effect of VX-445, tezacaftor (TEZ), and ivacaftor (IVA) when dosed in triple combination (TC) in Cystic Fibrosis (CF) subjects 6 through 11 years of age with F/F and F/MF genotypes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cystic Fibrosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

71 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part A: ELX/TEZ/IVA

Arm Type

Experimental

Arm Description

Participants in Part A received ELX 100 milligrams (mg) once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) in the treatment period for 15 days.

Arm Title

Part B: ELX/TEZ/IVA

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

ELX/TEZ/IVA

Other Intervention Name(s)

VX-445/VX-661/VX-770, elexacaftor/tezacaftor/ivacaftor

Intervention Description

Fixed-dose combination tablet orally once daily in the morning.

Intervention Type

Drug

Intervention Name(s)

IVA

Other Intervention Name(s)

VX-770, ivacaftor

Intervention Description

IVA tablet orally once daily in the evening.

Primary Outcome Measure Information:

Title

Part A: Maximum Observed Plasma Concentration (Cmax) of ELX, TEZ, and IVA

Time Frame

Part A: Day 15

Title

Part A: Observed Pre-dose Plasma Concentration (Ctrough) of ELX, TEZ, and IVA

Time Frame

Part A: Day 15

Title

Part A: Area Under the Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24h) of ELX, TEZ, and IVA

Time Frame

Part A: Day 15

Title

Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Time Frame

Part B: Day 1 Through Safety Follow-up Visit (up to Week 28)

Secondary Outcome Measure Information:

Title

Part A: Cmax of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)

Time Frame

Part A: Day 15

Title

Part A: Ctrough of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)

Time Frame

Part A: Day 15

Title

Part A: AUC0-24h of ELX Metabolite (M23-ELX) and TEZ Metabolite (M1-TEZ)

Time Frame

Part A: Day 15

Title

Part A: Area Under the Concentration Versus Time Curve From 0 to 6 Hours (AUC0-6h) of IVA Metabolite (M1-IVA)

Description

The AUC data was analyzed for up to 6 hours for IVA metabolite (M1-IVA). Therefore, AUC0-6h is reported for M1-IVA metabolite.

Time Frame

Part A: Day 15

Title

Part A: Safety and Tolerability as Assessed by Number of Participants With TEAEs and SAEs

Time Frame

Part A: Day 1 Through Safety Follow-up Visit (up to Day 43)

Title

Part B: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Description

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Time Frame

Part B: From Baseline Through Week 24

Title

Part B: Absolute Change in Sweat Chloride (SwCl)

Description

Sweat samples were collected using an approved collection device.

Time Frame

Part B: From Baseline Through Week 24

Title

Part B: Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score

Description

Time Frame

Part B: From Baseline Through Week 24

Title

Part B: Absolute Change in Body Mass Index (BMI)

Description

BMI was defined as weight in kg divided by squared height in meters (m^2).

Time Frame

Part B: From Baseline at Week 24

Title

Part B: Absolute Change in BMI For-Age Z-Score

Description

Time Frame

Part B: From Baseline at Week 24

Title

Part B: Absolute Change in Weight

Time Frame

Part B: From Baseline at Week 24

Title

Part B: Absolute Change in Weight-for-age Z-Score

Description

Time Frame

Part B: From Baseline at Week 24

Title

Part B: Absolute Change in Height

Time Frame

Part B: From Baseline at Week 24

Title

Part B: Absolute Change in Height-for-Age Z-Score

Description

Time Frame

Part B: From Baseline at Week 24

Title

Part B: Drug Acceptability Assessment Using Modified Facial Hedonic Scale

Description

Time Frame

Part B: At Week 24

Title

Part B: Number of Pulmonary Exacerbations Events

Description

Time Frame

Part B: From Baseline Through Week 24

Title

Part B: Number of CF Related Hospitalizations

Description

The total number of CF related hospitalization events across all participants were reported.

Time Frame

Part B: From Baseline Through Week 24

Title

Part B: Ctrough of ELX, ELX Metabolite (M23-ELX), TEZ, TEZ Metabolite (M1-TEZ), IVA and IVA Metabolite (M1-IVA)

Time Frame

Part B: At Week 4

Title

Part B: Absolute Change in Lung Clearance Index 2.5 (LCI2.5)

Description

LCI 2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.

Time Frame

Part B: From Baseline Through Week 24

10. Eligibility

Sex

All

Minimum Age & Unit of Time

6 Years

Maximum Age & Unit of Time

11 Years

Accepts Healthy Volunteers

Eligibility Criteria

Key Inclusion Criteria: Homozygous or heterozygous for F508del mutation (F/F or F/MF genotypes) Forced expiratory volume in 1 second (FEV1) value ≥40% of predicted mean for age, sex, and height. Key Exclusion Criteria: Clinically significant cirrhosis with or without portal hypertension Lung infection with organisms associated with a more rapid decline in pulmonary status. Solid organ or hematological transplantation. Other protocol defined Inclusion/Exclusion criteria may apply.

Facility Information:

Facility Name

Children's Hospital of Orange County

City

Orange

State/Province

California

ZIP/Postal Code

92868

Country

United States

Facility Name

Children's Hospital Colorado

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

Ann & Robert Lurie Children's Hospital of Chicago

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

Facility Name

Boston Children's Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Children's Respiratory and Critical Care Specialists, P.A., Children's Hospitals and Clinics of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55404

Country

United States

Facility Name

The Children's Mercy Hospital

City

Kansas City

State/Province

Missouri

ZIP/Postal Code

64108

Country

United States

Facility Name

Northwell Health- Long Island Jewish Medical Center

City

New Hyde Park

State/Province

New York

ZIP/Postal Code

11040

Country

United States

Facility Name

Clinical Research of Charlotte

City

Charlotte

State/Province

North Carolina

ZIP/Postal Code

28277

Country

United States

Facility Name

Rainbow Babies and Children's Hospital/University Hospitals Cleveland Medical Center

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44106

Country

United States

Facility Name

Nationwide Children's Hospital

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43205

Country

United States

Facility Name

Oregon Health & Science University

City

Portland

State/Province

Oregon

ZIP/Postal Code

97239

Country

United States

Facility Name

Texas Children's Hospital

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Seattle Children's Hospital

City

Seattle

State/Province

Washington

ZIP/Postal Code

98105

Country

United States

Facility Name

Queensland Children's Hospital

City

South Brisbane

Country

Australia

Facility Name

The Children's Hospital at Westmead

City

Westmead

Country

Australia

Facility Name

The Hospital for Sick Children

City

Toronto

Country

Canada

Facility Name

British Columbia's Children's Hospital

City

Vancouver

Country

Canada

Facility Name

Children's Health Ireland at Crumlin

City

Dublin

Country

Ireland

Facility Name

Children's Health Ireland at Temple Street

City

Dublin

Country

Ireland

Facility Name

Birmingham Children's Hospital

City

Birmingham

Country

United Kingdom

Facility Name

Royal Brompton & Harefield NHS Foundation Trust, Royal Brompton Hospital

City

London

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

33734030

Citation

Zemanick ET, Taylor-Cousar JL, Davies J, Gibson RL, Mall MA, McKone EF, McNally P, Ramsey BW, Rayment JH, Rowe SM, Tullis E, Ahluwalia N, Chu C, Ho T, Moskowitz SM, Noel S, Tian S, Waltz D, Weinstock TG, Xuan F, Wainwright CE, McColley SA. A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele. Am J Respir Crit Care Med. 2021 Jun 15;203(12):1522-1532. doi: 10.1164/rccm.202102-0509OC.

Results Reference

derived

PubMed Identifier

33331662

Citation

Southern KW, Murphy J, Sinha IP, Nevitt SJ. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev. 2020 Dec 17;12(12):CD010966. doi: 10.1002/14651858.CD010966.pub3.

Results Reference

derived

Learn more about this trial

Evaluation of VX 445/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age

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